Monoclonal antibodies that block inhibitory T-cell receptors (PD-1, PD-L1, CTLA-4, LAG-3) → releasing the immune system against tumour cells. Used across most solid tumours and some haematologic malignancies. Anti-PD-1/PD-L1 agents are the workhorses; anti-CTLA-4 is more toxic but synergistic in combination.

comparison

	Anti-PD-1	Anti-PD-L1	Anti-CTLA-4	Anti-LAG-3
Agents	pembrolizumab, nivolumab, cemiplimab, dostarlimab	atezolizumab, durvalumab, avelumab	ipilimumab, tremelimumab	relatlimab
Mechanism	blocks PD-1 on T cells → prevents tumour PD-L1 from switching T cells off	blocks PD-L1 on tumour/APC → same effect from the ligand side	blocks CTLA-4 → enhances T-cell priming and activation (earlier in immune response)	blocks LAG-3 on T cells → similar to PD-1 blockade, restores exhausted T cells
Toxicity profile	moderate - pneumonitis, thyroiditis, hepatitis	similar to anti-PD-1	highest toxicity - colitis, hypophysitis; grade ≥3 irAEs ~20–30% monotherapy, ~40–55% in combination with anti-PD-1	similar to anti-PD-1
Typical use	broadest indications: first-line across most solid tumours	NSCLC (durvalumab post-CRT), urothelial, TNBC	melanoma, RCC; almost always combined with anti-PD-1	melanoma (combined with nivolumab)

administration

IV infusion 30–60 min; no routine premedication (no antiemetics or steroids); infusion reactions uncommon (~1–2%)
no renal or hepatic dose adjustments as antibodies cleared by catabolism
no myelosuppression: fever on ICI monotherapy is not neutropenic fever; think infection vs irAE (or, if on chemo-immunotherapy, the chemo)
avoid systemic corticosteroids at ICI initiation (prednisone ≤10 mg/day or physiologic replacement is acceptable): baseline steroids may blunt anti-tumour response. When steroids are needed to treat irAEs, give them — toxicity management takes priority
treatment typically continues up to 2 years or until progression/toxicity; responses are often durable, persisting after discontinuation

pseudoprogression

A minority of patients show apparent radiographic growth (immune infiltrate) before response. Uncommon (<10%), but a clinically well patient with early “progression” may continue with repeat imaging rather than stopping.

All ICIs cause irAEs — see immune checkpoint inhibitor toxicity

Any new symptom in a patient on ICI is an irAE until proven otherwise.

Class	Common irAEs	Distinguishing features
Anti-PD-1 / PD-L1	thyroiditis (up to 20%), rash, hepatitis, pneumonitis	pneumonitis is the signature severe toxicity; thyroiditis often subclinical
Anti-CTLA-4	diarrhoea (~30–40%), true colitis (~10–15%), hypophysitis (10–15%), rash, hepatitis	colitis is the signature toxicity — can be severe/perforating; any diarrhoea on ipilimumab needs investigation. Hypophysitis relatively specific to CTLA-4 blockade
Anti-LAG-3	similar to anti-PD-1	no unique toxicity signal
Combination (PD-1 + CTLA-4)	all of the above at higher rates	grade ≥3 in ~40–55%; earlier onset; more multi-organ toxicity

Common nuisance irAEs — fatigue, arthralgia, pruritus/rash — are frequent and usually manageable without stopping treatment.

timing

most irAEs present weeks 6–12 of treatment
skin and GI (colitis) tend to be earlier; hepatic, pulmonary, and endocrine later
irAEs can present months after discontinuation

high-risk irAEs to know

myocarditis: rare (<1%) but up to 50% mortality; troponin + new conduction abnormality → ICU, pulse steroids. Often part of an overlap syndrome with myositis and myasthenia gravis; check CK and screen for ptosis/bulbar weakness
pneumonitis: low index of suspicion for all new dyspnoea on ICI, often need to treat as pneumonitis until proven otherwise
neurological: myasthenia-like syndrome, GBS, encephalitis; rare but rapidly progressive
nephritis: immune interstitial nephritis (rising creatinine on ICI often misattributed to contrast, NSAIDs, or PPI). Diagnosis often requires biopsy
immune-mediated DKA: sudden autoimmune beta-cell destruction; lifelong insulin
colitis: particularly with ipilimumab; can perforate
hypophysitis: particularly with ipilimumab; immune destruction of the pituitary → panhypopituitarism; presents with fatigue, headache, visual changes, adrenal insufficiency
adrenalitis: primary adrenal insufficiency from direct glandular destruction; unlike hypophysitis, ACTH is elevated

endocrine gland destruction

Steroids won’t restore the damaged gland; treatment will involve lifelong hormone replacement.

Gland destroyed	Replacement
Thyroid (thyroiditis → hypothyroidism)	levothyroxine
Pituitary (hypophysitis)	hydrocortisone + levothyroxine ± testosterone/oestrogen ± desmopressin
Adrenal (adrenalitis)	hydrocortisone ± fludrocortisone
Pancreatic beta cells (immune DKA)	insulin

adrenal insufficiency

Both hypophysitis (secondary) and adrenalitis (primary) lead to adrenal insufficiency. Check AM cortisol and ACTH before starting levothyroxine: thyroid replacement increases cortisol clearance and can precipitate adrenal crisis. Remember to educate patient on steroid sick day rules.

management principles

Severity is graded by CTCAE (organ-specific criteria): in broad strokes, · 1 = mild/asymptomatic · 2 = moderate, limits daily activities · 3 = severe, hospitalisation usually indicated · 4 = life-threatening.

grade ≥3 → hold ICI + high-dose systemic corticosteroids (methylprednisolone 1–2 mg/kg/day; pulse for myocarditis); taper over ≥4–6 weeks once grade ≤1
steroid-refractory (no improvement 48–72 h) → escalate to targeted immunosuppression — see immune checkpoint inhibitor toxicity
endocrine irAEs: steroids do not reverse glandular destruction; definitive treatment is hormone replacement, and ICI can usually resume once stable on replacement
rechallenge: generally not after grade 4 irAEs, most recurrent grade 3, or any myocarditis/severe neurological irAE; may be possible after grade 2 and endocrine irAEs

special populations

pre-existing autoimmune disease: relative, not absolute, contraindication; flare risk ~30–50%, usually manageable. Decision depends on disease severity and cancer prognosis
solid organ transplant: high risk of graft rejection (~40% in kidney transplant); ICI generally avoided unless no alternative; always involve the transplant team
immunosuppressed patients (chronic steroids >10 mg prednisone, biologics): may blunt efficacy; optimise before starting if feasible

key points

anti-PD-1 (pembrolizumab, nivolumab) are the backbone of modern immunotherapy and are used across most solid tumours; often combined with chemotherapy first-line (NSCLC, TNBC, gastric, oesophageal)
anti-CTLA-4 (ipilimumab) is rarely used alone; combined with anti-PD-1 in melanoma, RCC, NSCLC; effective but substantially more toxic
ICI → no myelosuppression, no premeds, no dose adjustments
any new symptom on ICI is an irAE until proven otherwise; have low threshold to hold and investigate; irAEs can present months after discontinuation
endocrine irAEs need replacement, not steroids; check cortisol/ACTH before levothyroxine
caution in autoimmune disease, essentially contraindicated in most transplant recipients